Throughout this application, various publications are referenced. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Several 9-acridones have been found to exhibit anticancer activity. 9-Acridone derivatives with or without a dialkylaminoalkyl side chain attached to the N-position were synthesized and studied for their antitumor activity (Radzikowski et al., Archvm. Immunol. Ther. Exp. 1971; 19: 219). Among these, N-(N-dialkylamino)ethyl-1-nitro-9-acridones were shown to have antitumor activity in the S-180 system in vivo and these have undergone extensive preclinical testing (Pelczarska et al., Archvm. Immumnol. Ther. Exp. 1973; 22: 823). It Was also reported that the bis-cationic side-chain substituted 9-acridone can act as an acceptable chromophore for DNA intercalation. (Wright et al., Biochemistry 1980; 19: 5825).
Recently, the structure-activity relationships of fifty natural acridone alkaloids for their effects on the inhibition of cell growth and macromolecule biosynthesis of human promyelocytic leukemic cells has been studied. (Chou et al., Phytotherapy Res. 1989; 3: 237). It was found that twenty three out of the fifty alkaloids were more active than acronycine, an antineoplastic alkaloid used in clinical trails (Svoboda et al., J. Pharm. Sci. 1966; 55: 758-768). For inhibition of cell growth of human leukemic HL-60 cell lines in vitro, the most potent compound in this series was TSA-35 (1,6-dihydroxy-2,3,4,5-tetramethoxy-10-methyl-9-acridone, or glyfoline), with IC.sub.50 of 1.1 .mu.M. TSA-35 was originally isolated from Glycosmic citrifolia (Wild.) Lindl. (Rutaceae) in a minute amount by Wu et al. (Wu, T. S. and Furukawa, H., Heterocycles 1982; 19: 1047). It has not been reported to date that the known natural alkaloid, 1,6-hydroxy-2,3,4,5-tetramethoxy-9-acridone exhibits antitumor activity. The chemical synthesis of this alkaloid and structurally similar compounds also has not been reported to date.